5-1880777-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016358.3(IRX4):c.355G>A(p.Ala119Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,613,276 control chromosomes in the GnomAD database, including 30,377 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3015 hom., cov: 31)

Exomes 𝑓: 0.19 ( 27362 hom. )

Consequence

IRX4
NM_016358.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.73

Publications

15 publications found

Variant links:

Genes affected

IRX4 (HGNC:6129): (iroquois homeobox 4) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in cell development; neuron differentiation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within heart development. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

IRX4 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
ventricular septal defect 1
Inheritance: AD Classification: LIMITED Submitted by: Illumina

IRX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017234981).

BP6

Variant 5-1880777-C-T is Benign according to our data. Variant chr5-1880777-C-T is described in ClinVar as Benign. ClinVar VariationId is 1280723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRX4	NM_016358.3 link	c.355G>A	p.Ala119Thr	missense_variant	Exon 3 of 5	ENST00000231357.7	NP_057442.1	P78413-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRX4	ENST00000231357.7 link	c.355G>A	p.Ala119Thr	missense_variant	Exon 3 of 5	1	NM_016358.3	ENSP00000231357.2		P78413-1

Frequencies

GnomAD3 genomes

AF:

0.194

AC:

29502

AN:

151854

Hom.:

3001

Cov.:

show subpopulations

Gnomad AFR

AF:

0.227

Gnomad AMI

AF:

0.0945

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.298

Gnomad EAS

AF:

0.00600

Gnomad SAS

AF:

0.0862

Gnomad FIN

AF:

0.190

Gnomad MID

AF:

0.205

Gnomad NFE

AF:

0.203

Gnomad OTH

AF:

0.198

GnomAD2 exomes

AF:

0.167

AC:

41884

AN:

251104

AF XY:

0.166

show subpopulations

Gnomad AFR exome

AF:

0.235

Gnomad AMR exome

AF:

0.111

Gnomad ASJ exome

AF:

0.291

Gnomad EAS exome

AF:

0.00729

Gnomad FIN exome

AF:

0.192

Gnomad NFE exome

AF:

0.202

Gnomad OTH exome

AF:

0.187

GnomAD4 exome

AF:

0.188

AC:

274538

AN:

1461306

Hom.:

27362

Cov.:

AF XY:

0.185

AC XY:

134771

AN XY:

726986

show subpopulations

African (AFR)

AF:

0.231

AC:

7728

AN:

33470

American (AMR)

AF:

0.115

AC:

5149

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

7548

AN:

26130

East Asian (EAS)

AF:

0.00715

AC:

284

AN:

39700

South Asian (SAS)

AF:

0.0967

AC:

8340

AN:

86254

European-Finnish (FIN)

AF:

0.187

AC:

9945

AN:

53114

Middle Eastern (MID)

AF:

0.243

AC:

1400

AN:

5768

European-Non Finnish (NFE)

AF:

0.201

AC:

222999

AN:

1111776

Other (OTH)

AF:

0.185

AC:

11145

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

11093

22187

33280

44374

55467

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7604

15208

22812

30416

38020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.194

AC:

29541

AN:

151970

Hom.:

3015

Cov.:

AF XY:

0.191

AC XY:

14221

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.227

AC:

9412

AN:

41390

American (AMR)

AF:

0.149

AC:

2282

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.298

AC:

1031

AN:

3464

East Asian (EAS)

AF:

0.00601

AC:

AN:

5156

South Asian (SAS)

AF:

0.0861

AC:

414

AN:

4810

European-Finnish (FIN)

AF:

0.190

AC:

2011

AN:

10588

Middle Eastern (MID)

AF:

0.210

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.203

AC:

13802

AN:

67976

Other (OTH)

AF:

0.195

AC:

411

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1162

2324

3486

4648

5810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

312

624

936

1248

1560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.200

Hom.:

12984

Bravo

AF:

0.194

TwinsUK

AF:

0.187

AC:

693

ALSPAC

AF:

0.189

AC:

727

ESP6500AA

AF:

0.230

AC:

1014

ESP6500EA

AF:

0.203

AC:

1742

ExAC

AF:

0.166

AC:

20105

Asia WGS

AF:

0.0650

AC:

226

AN:

3478

EpiCase

AF:

0.216

EpiControl

AF:

0.212

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 10, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.070

T;T;.;.;T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.68

.;T;.;T;.;T

MetaRNN

Benign

0.0017

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;N;N;N;N;.

PhyloP100

2.7

PrimateAI

Uncertain

0.76

PROVEAN

Benign

0.040

N;N;.;.;N;N

REVEL

Benign

0.074

Sift

Benign

0.58

T;T;.;.;T;T

Sift4G

Benign

0.45

T;T;T;T;T;T

Polyphen

0.58

P;P;.;.;P;.

Vest4

0.31

MPC

0.59

ClinPred

0.013

GERP RS

4.0

Varity_R

0.093

gMVP

0.70

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over